Mitochondrial Reactive Oxygen Species Mediate Activation of TRPV1 and Calcium Entry Following Peripheral Sensory Axotomy.
Axons that are physically separated from their soma activate a series of signaling events that results in axonal self-destruction. A critical element of this signaling pathway is an intra-axonal calcium rise that occurs just prior to axonal fragmentation. Previous studies have shown that preventing this calcium rise delays the onset of axon fragmentation, yet the ion channels responsible for the influx, and the mechanisms by which they are activated, are largely unknown. Axonal injury can be modeled in vitro by transecting murine dorsal root ganglia (DRG) sensory axons. We coupled transections with intra-axonal calcium imaging and found that Ca2+ influx is sharply reduced in axons lacking trpv1 (for transient receptor potential cation channel vanilloid 1) and in axons treated with capsazepine (CPZ), a TRPV1 antagonist. Sensory neurons from trpv1 -/- mice were partially rescued from degeneration after transection, indicating that TRPV1 normally plays a pro-degenerative role after axonal injury. TRPV1 activity can be regulated by direct post-translational modification induced by reactive oxygen species (ROS). Here, we tested the hypothesis that mitochondrial ROS production induced by axotomy is required for TRPV1 activity and subsequent axonal degeneration. We found that reducing mitochondrial depolarization with NAD+ supplementation or scavenging ROS using NAC or MitoQ sharply attenuates TRPV1-dependent calcium influx induced by axotomy. This study shows that ROS-dependent TRPV1 activation is required for Ca2+ entry after axotomy.


Risk factors effecting mortality in acute mesenteric ischemia and mortality rates: a single center experience.
The objective of this study is to discuss the effective factors on morbidity and mortality in patients who were operated on for acute mesenteric ischemia. Between 2006 and 2011, 95 patients, who underwent emergent surgery for acute mesenteric ischemia, were analyzed retrospectively. The study group consisted of 56 men (58.9%) and 39 women (41.1%), with an average age of 68.4 ± 14.4 years. Elapsed time between the onset of the symptoms and the surgical operation was less than 24 hours in 47 (49.5%) cases, and more than 24 hours in 48 cases (50.5%) (P < 0.001). Although all of the patients had intestinal necroses, colon involvement was seen in 38 patients, and mortality was higher in this group of patients (P < 0.001). Mortality rate was 42.1%. This was higher in older patients, those with increased leukocyte levels, increased elapsed time to laparotomy, and when the colon was involved.


Oral supplementation with selected Lactobacillus acidophilus triggers IL-17-dependent innate defense response, activation of innate lymphoid cells type 3 and improves colitis.
Live biotherapeutic products constitute an emerging therapeutic approach to prevent or treat inflammatory bowel diseases. Lactobacillus acidophilus is a constituent of the human microbiota with probiotic potential, that is illustrated by improvement of intestinal inflammation and antimicrobial activity against several pathogens. In this study, we evaluated the immunomodulatory properties of the L. acidophilus strain BIO5768 at steady state and upon acute inflammation. Supplementation of naïve mice with BIO5768 heightened the transcript level of some IL-17 target genes encoding for protein with microbicidal activity independently of NOD2 signaling. Of these, the BIO5768-induced expression of Angiogenin-4 was blunted in monocolonized mice that are deficient for the receptor of IL-17 (but not for NOD2). Interestingly, priming of bone marrow derived dendritic cells by BIO5768 enhanced their ability to support the secretion of IL-17 by CD4+ T cells. Equally of importance, the production of IL-22 by type 3 innate lymphoid cells is concomitantly heightened in response to BIO5768. When administered alone or in combination with Bifidobacterium animalis spp. lactis BIO5764 and Limosilactobacillus reuteri, BIO5768 was able to alleviate at least partially intestinal inflammation induced by Citrobacter rodentium infection. Furthermore, BIO5768 was also able to improve colitis induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS). In conclusion, we identify a new potential probiotic strain for the management of inflammatory bowel diseases, and provide some insights into its IL-17-dependent and independent mode of action.


Mother's Characteristics and Socioeconomic Status as Possible Risk Factors for Children's Caries in Jordan.
Clinical oral health status of children affects their health-related quality of life. A major determinant of oral health is early childhood caries, which possesses a negative effect. The primary objective of the study was to examine the association between socioeconomic status and different mother's characteristics and the risk of dental caries in children using the decay missing filled (DMF) score as an indicator. This was a cross-sectional descriptive study that was in the pediatric dental clinic in Hashem Ibn Al-Hussein medical military hospital in Jordan. Pearson correlation was used to examine associations between two continuous variables. Linear regression was used to detect variables that might predict the decayed missing filled teeth (dmft) score of the child. A total of 264 children were enrolled in the study. Average age of children was 4.80 ± 1.99 years, and average mothers' age was 32.74 ± 5.68. Mothers had an average DMFT score of 8.84 ± 5.39, while children had an average dmft score of 6.17 ± 4.82. There was no association between the mother's age and the dmft score of the child (Pearson correlation = 0.08, and P value = 0.215). However, a moderate, statistically significant correlation was found between the mother's and the child's DMFT scores (Pearson correlation = 0.418, and P value = 0.001). Children who belonged to low and middle-income families had a higher dmft score compared to those that belonged to families with high income. Socioeconomic status of the family, mother's habits, dental hygiene, and education level are important factors that influence the child's oral health. Strategies that focus on children with these characteristics can help them achieve better oral health.


Cytokine promoter polymorphisms in severe sepsis.
The need to develop individualized risk profiles and drug therapy regimens motivates interest in genetic studies of critically ill patients. Gene promoter variants may predict interindividual variability in response to inflammatory stimuli, such as infection and trauma. Genomic variations also may affect gene expression profiles, as well as the structure and production of proteins. The genes involved in inflammation are numerous, as are genomic variations within most of those genes. Cytokine genes involved in inflammatory cascades are important candidate genes that may determine the extent of a person's response to injury. Understanding the genetic determination of the inflammatory process includes the possibility of developing valuable diagnostic tools and new therapeutic approaches in severe sepsis. To date, specific patterns of markers of genomic variation reliably indicating at-risk populations do not exist. Evaluation of possible genomic markers for risk stratification of patients with sepsis and persons at high risk of developing organ failure has begun at a level of well-powered genetic epidemiological research. Cytokine promoter variants may contribute substantially to studies of genetic predisposition of sepsis because they operate in a gene region of high regulatory activity.


Pitch Shifting With the Commercially Available Eventide Eclipse: Intended and Unintended Changes to the Speech Signal.
Purpose This study details the intended and unintended consequences of pitch shifting with the commercially available Eventide Eclipse. Method Ten vocally healthy participants ( M = 22.0 years; 6 cisgender females, 4 cisgender males) produced a sustained /ɑ/, creating an input signal. This input signal was processed in near real time by the Eventide Eclipse to create an output signal that was either not shifted (0 cents), shifted +100 cents, or shifted -100 cents. Shifts occurred either throughout the entire vocalization or for a 200-ms period after vocal onset. Results Input signals were compared to output signals to examine potential changes. Average pitch-shift magnitudes were within 1 cent of the intended pitch shift. Measured pitch-shift length for intended 200-ms shifts was between 5.9% and 21.7% less than expected, based on the portion of shift selected for measurement. The delay between input and output signals was an average of 11.1 ms. Trials shifted +100 cents had a longer delay than trials shifted -100 or 0 cents. The first 2 formants (F1, F2) shifted in the direction of the pitch shift, with F1 shifting 6.5% and F2 shifting 6.0%. Conclusions The Eventide Eclipse is an accurate pitch-shifting hardware that can be used to explore voice and vocal motor control. The pitch-shifting algorithm shifts all frequencies, resulting in a subsequent change in F1 and F2 during pitch-shifted trials. Researchers using this device should be mindful of stimuli selection to avoid confusion during data interpretation.


Accelerating Maturation of Spatial Memory Systems by Experience: Evidence from Sleep Oscillation Signatures of Memory Processing.
During early development, memory systems gradually mature over time, in parallel with the gradual accumulation of knowledge. Yet, it is unknown whether and to what extent maturation is driven by discrete experience. Sleep is thought to contribute to the formation of long-term memory and knowledge through a systems consolidation process that is driven by specific sleep oscillations (i.e., ripples, spindles, and slow oscillations) in cortical and hippocampal networks. Based on these oscillatory signatures, we show here in rats that discrete spatial experience speeds the functional maturation of spatial memory systems during development. Juvenile male rats were exposed for 5 min periods to changes in the spatial configuration of two identical objects on postnatal day (PD)25, PD27, and PD29 (Spatial experience group), while a Control group was exposed on these occasions to the same two objects without changing their positions. On PD31, both groups were tested on a classical Object Place Recognition (OPR) task with a 3 h retention interval during which the sleep-associated EEG and hippocampal local field potentials were recorded. On PD31, consistent with forgoing studies, Control rats still did not express OPR memory. By contrast, rats with Spatial experience formed significant OPR memory and, in parallel, displayed an increased percentage of hippocampal ripples coupled to parietal slow oscillation-spindle complexes, and a stronger ripple-spindle phase-locking during the retention sleep. Our findings support the idea that experience promotes the maturation of memory systems during development by enhancing cortico-hippocampal information exchange and the formation of integrated knowledge representations during sleep.SIGNIFICANCE STATEMENT Cognitive and memory capabilities mature early in life. We show here that and how discrete spatial experience contributes to this process. Using a simple recognition paradigm in developing rats, we found that exposure of the rat pups to three short-lasting experiences enhances spatial memory capabilities to adult-like levels. The adult-like capability of building spatial memory was connected to a more precise coupling of ripples in the hippocampus with slow oscillation-spindle complexes in the thalamo-cortical system when the memory was formed during sleep. Our findings support the view that discrete experience accelerates maturation of cognitive and memory capabilities by enhancing the dialogue between hippocampus and cortex when these experiences are reprocessed during sleep.


[Study on knowledge and practices related to malnutrition in the elderly to the nursing home].
The prevalence of malnutrition in nursing homes varies between 50% and 90% in Belgium. There are multiple causes of malnutrition and one of the consequences is the impact on the workload of nursing home staff. The purpose of this study is to better understand the knowledge and the practices of the nursing home staff who would influence the nutritional status of elderly in nursing homes. This study is divided into a quantitative approach with a self-administered questionnaire and a qualitative approach by non-participant observation. We observed that 29% of nursing home staff have good knowledge about the malnutrition and that 64% have good practices in providing nutrition to the elderly. People with good knowledge tend to have better practices. 38% of the nursing home staff engage in continued professional development in the field. There is no systematic screening, nutritional assessment and nutritional intervention in nursing homes. It is of great importance to ensure nursing home staff are aware of this problem through training.


Digitally Guided Direct Composite Injection Technique with a Bi-layer Clear Mini-Index for the Management of Extensive Occlusal Caries in a Pediatric Patient: A Case Report.
This case report presents a direct composite inverse injection technique using a bi-layer clear mini-index fabricated with a digital workflow to restore extensive posterior occlusal cavities in a 13-year-old patient. After a root canal treatment in the right mandibular first molar and step-wise excavation of deep caries in the left mandibular first molar, the extensive occlusal restorations were digitally designed using CAD software, upon which digital wax-ups were 3D-printed. Bi-layer clear mini-indices consisting of a hard outer plastic layer and an elastic inner silicone layer were prepared from the 3D-printed cast. The bonding surfaces were deproteinized using a 6% sodium hypochlorite solution, and an antioxidant (Clearfil DC Activator; Kuraray Noritake) was utilized to improve the dentin bonding durability of a 2-step self-etch adhesive (Clearfil SE Bond 2; Kuraray Noritake). Subsequently, a highly filled universal-shade flowable resin composite (RC) was incrementally placed into the cavities. To create the final occlusal morphology, the same RC was inversely injected through the opening of the bi-layer indices. The workflow was feasible, and the occlusal cavities were efficiently restored using the injection technique. Occlusal carving and adjustments of the morphology were not necessary, leading to less chair time. At the 1-year follow-up, the clinical outcome was excellent. The injection technique with a bi-layer clear mini-index accurately translated the digital wax-ups into large, final restorations. Precise morphology and shortened chair time enhanced patient satisfaction, but at the expense of multiple visits.


ADAM33, a new candidate for psoriasis susceptibility.
Psoriasis is a chronic skin disorder with multifactorial etiology. In a recent study, we reported results of a genome-wide scan on 46 French extended families presenting with plaque psoriasis. In addition to unambiguous linkage to the major susceptibility locus PSORS1 on Chromosome 6p21, we provided evidence for a susceptibility locus on Chromosome 20p13. To follow up this novel psoriasis susceptibility locus we used a family-based association test (FBAT) for an association scan over the 17 Mb candidate region. A total of 85 uncorrelated SNP markers located in 65 genes of the region were initially investigated in the same set of large families used for the genome wide search, which consisted of 295 nuclear families. When positive association was obtained for a SNP, candidate genes nearby were explored more in detail using a denser set of SNPs. Thus, the gene ADAM33 was found to be significantly associated with psoriasis in this family set (The best association was on a 3-SNP haplotype P = 0.00004, based on 1,000,000 permutations). This association was independent of PSORS1. ADAM33 has been previously associated with asthma, which demonstrates that immune system diseases may be controlled by common susceptibility genes with general effects on dermal inflammation and immunity. The identification of ADAM33 as a psoriasis susceptibility gene identified by positional cloning in an outbred population should provide insights into the pathogenesis and natural history of this common disease.


The Ontario Air Pollution Study: identification of the causative agent.
Previously published data from the Ontario Air Pollution study are reviewed. It has been shown that there is a consistent association in summer between hospital admissions for respiratory disease in Southern Ontario, and daily levels of SO4, O3, and temperature. No association exists for a group nonrespiratory conditions. Multiple regression analyses are presented that show all environmental variables account for 5.6% of the variability in respiratory admissions and that if temperature is forced into the analysis first, it accounts for 0.89% of the variability only. Distribution plots of standardized residuals are presented. In June of 1983, there were an exceptional number of ozone episodes (defined as occasions when ozone was greater than 82 ppb for 3 or more hours in a calendar day) in this region. A separate analysis of hospital admissions for acute respiratory diseases for the month of June for several years shows no demonstrable excess in June of 1983; previously regional analyses have indicated that ozone is associated with increased levels in July and August over a 9-year period. It has also been found that daily SO4 data collected at one monitoring site in the center of the region are not correlated with respiratory admissions, whereas the SO4 values collected every sixth day, on different days of the week, at 17 stations in the region had the highest correlation with respiratory admissions.(ABSTRACT TRUNCATED AT 250 WORDS)


Quantitative analysis of particulate burden in lung tissue.
Numerous methods have been used in the preparation and analysis of the particulate matter deposited in human lungs. Preparation techniques include those for particle isolation and for in situ analysis. Analytical techniques include bulk and particle-by-particle analysis. In this paper, a general discussion of many of these methods is presented along with examples of how two specific techniques have been used. In one study, individual particles from the lungs of 75 randomly selected autopsy cases were analyzed using an automated scanning electron microscopy (SEM)/energy dispersive X-ray microanalysis (EDX) system. An average of 613 million particles, of exogenous origin, per gram of dry lung tissue were found, the major classes of particles being silica, talc, aluminum silicates, and rutile. In the second study, lungs from 50 randomly selected autopsy cases were analyzed using gravimetric and X-ray diffraction (XRD) analysis. The median total particulate material was 0.33 grams, for cases in which samples were prepared by high temperature ashing, and 0.41 grams, for those in which nitric acid digestion was used. The median amount of quartz for all cases, was 0.044 grams. Samples of eighteen of the 75 lungs previously analyzed by automated SEM/EDX were also analyzed using gravimetric and XRD analysis. A good correlation was seen between the results of the two procedures (r = 0.91 for number of exogenous particles versus grams of particulate matter and r = 0.97 for number of silica particles versus amount of quartz).


Formation of Flower Fragrance Compounds from Their Precursors by Enzymic Action during Flower Opening.
Flower fragrance compounds were found to be produced from the precursor solution obtained from flower buds by crude enzyme prepared from the flowers at the opening stage. GC and GC-MS analyses showed the formation of volatile aroma constituents from the precursor solution of Jasminum polyanthum F, Jasminum sambac Ait, and Gardenia jasminoides E, but none in the case of Osmanthus fragrans L. The aroma-producing enzyme activity of G. jasminoides rapidly increased to reach the maximum at flower opening stage (stage 4) and decreased within 24 h after flower opening (stage 5). Fragrance precursors of G. jasminoides were suggested not to be mainly β-glucosides of linalool, eugenol, borneol, and isoeugenol based on the results after β-glucosidase and naringinase treatment of the precursor solution. The activity of hydrolytic enzyme(s) such as glycosidase was found to elevate during flower opening to result in the aroma formation.


The characterization of novel mycorrhiza-specific phosphate transporters from Lycopersicon esculentum and Solanum tuberosum uncovers functional redundancy in symbiotic phosphate transport in solanaceous species.
Solanaceous species are among the >200 000 plant species worldwide forming a mycorrhiza, that is, a root living in symbiosis with soil-borne arbuscular-mycorrhizal (AM) fungi. An important parameter of this symbiosis, which is vital for ecosystem productivity, agriculture, and horticulture, is the transfer of phosphate (Pi) from the AM fungus to the plant, facilitated by plasma membrane-spanning Pi transporter proteins. The first mycorrhiza-specific plant Pi transporter to be identified, was StPT3 from potato [Nature414 (2004) 462]. Here, we describe novel Pi transporters from the solanaceous species tomato, LePT4, and its orthologue StPT4 from potato, both being members of the Pht1 family of plant Pi transporters. Phylogenetic tree analysis demonstrates clustering of both LePT4 and StPT4 with the mycorrhiza-specific Pi transporter from Medicago truncatula [Plant Cell, 14 (2002) 2413] and rice [Proc. Natl Acad. Sci. USA, 99 (2002) 13324], respectively, but not with StPT3, indicating that two non-orthologous mycorrhiza-responsive genes encoding Pi transporters are co-expressed in the Solanaceae. The cloned promoter regions from both genes, LePT4 and StPT4, exhibit a high degree of sequence identity and were shown to direct expression exclusively in colonized cells when fused to the GUS reporter gene, in accordance with the abundance of LePT4 and StPT4 transcripts in mycorrhized roots. Furthermore, extensive sequencing of StPT4-like clones and subsequent expression analysis in potato and tomato revealed the presence of a close paralogue of StPT4 and LePT4, named StPT5 and LePT5, respectively, representing a third Pi transport system in solanaceous species which is upregulated upon AM fungal colonization of roots. Knock out of LePT4 in the tomato cv. MicroTom indicated considerable redundancy between LePT4 and other Pi transporters in tomato.


[Spontaneous bilateral quadriceps tendon rupture in obese patient medicated with statin].
Bilateral quadriceps tendon rupture (BQTR) is a rare diagnosis only reported in about 100 cases in international literature, and is often associated with medical diseases, trauma or certain medications. We present a 64-year-old man with spontaneous BQTR, diagnosed and treated at our hospital. His risk factors were obesity (BMI = 30.95 kg/m2), statin use, and recreational tennis at time of injury. The diagnosis of BQTR is difficult and is often missed initially. There is also emerging thoughts that the use of statins may be a risk factor for BQTR. The evidence, however, is scarce.


In vitro antioxidant and, α-glucosidase inhibitory activities and comprehensive metabolite profiling of methanol extract and its fractions from Clinacanthus nutans.
This study was aimed to evaluate antioxidant and α-glucosidase inhibitory activity, with a subsequent analysis of total phenolic and total flavonoid content of methanol extract and its derived fractions from Clinacanthus nutans accompanied by comprehensive phytochemical profiling. Liquid-liquid partition chromatography was used to separate methanolic extract to get hexane, ethyl acetate, butanol and residual aqueous fractions. The total antioxidant activity was determined by 2,2-diphenyl-1-picrylhydrazy (DPPH) radical scavenging and ferric reducing antioxidant power assay (FRAP). The antidiabetic activity of methanol extract and its consequent fractions were examined by α-glucosidase inhibitory bioassay. The chemical profiling was carried out by gas chromatography coupled with quadrupole time-of-flight mass spectrometry (GC Q-TOF MS). The total yield for methanol extraction was (12.63 ± 0.98) % (w/w) and highest fractionated value found for residual aqueous (52.25 ± 1.01) % (w/w) as compared to the other fractions. Significant DPPH free radical scavenging activity was found for methanolic extract (63.07 ± 0.11) % and (79.98 ± 0.31) % for ethyl acetate fraction among all the fractions evaluated. Methanol extract was the most prominent in case of FRAP (141.89 ± 0.87 μg AAE/g) whereas most effective reducing power observed in ethyl acetate fraction (133.6 ± 0.2987 μg AAE/g). The results also indicated a substantial α-glucosidase inhibitory activity for butanol fraction (72.16 ± 1.0) % and ethyl acetate fraction (70.76 ± 0.49) %. The statistical analysis revealed that total phenolic and total flavonoid content of the samples had the significant (p < 0.05) impact on DPPH free radical scavenging and α-glucosidase inhibitory activity. Current results proposed the therapeutic potential of Clinacanthus nutans, especially ethyl acetate and butanol fraction as chemotherapeutic agent against oxidative related cellular damages and control the postprandial hyperglycemia. The phytochemical investigation showed the existence of active constituents in Clinacanthus nutans extract and fractions.


Occupation and thyroid cancer risk in Sweden.
The objective of this study was to identify occupations and industries with increased incidence of thyroid cancer in Swedish workers. Standardized incidence ratios were computed for each job and industry for the period 1971-1989 through record-linkage with the Swedish National Cancer and Death Registers. Age-, period-, geographically adjusted relative risks were calculated using Poisson models. Increased risks were found for teachers, construction carpenters, policemen, and prison/reformatory officials in men, and medical technicians, shop managers, tailors, and shoecutters among women. Industries with risk excess are manufacture of agricultural machinery, manufacture of computing/accessories, and public administration/police among men; and manufacture of prefabricated wooden buildings, electric installation work, and wholesale of live animals/fertilizers/oilseed/grain among women. Our results corroborate some previously reported increased risks. Further research is needed to assess the influence of specific chemical agents related with some of the highlighted work environments.


Cryo-EM structure of the hibernating Thermus thermophilus 100S ribosome reveals a protein-mediated dimerization mechanism.
In response to cellular stresses bacteria conserve energy by dimerization of ribosomes into inactive hibernating 100S ribosome particles. Ribosome dimerization in Thermus thermophilus is facilitated by hibernation-promoting factor (TtHPF). In this study we demonstrate high sensitivity of Tt100S formation to the levels of TtHPF and show that a 1:1 ratio leads to optimal dimerization. We report structures of the T. thermophilus 100S ribosome determined by cryo-electron microscopy to average resolutions of 4.13 Å and 4.57 Å. In addition, we present a 3.28 Å high-resolution cryo-EM reconstruction of a 70S ribosome from a hibernating ribosome dimer and reveal a role for the linker region connecting the TtHPF N- and C-terminal domains in translation inhibition by preventing Shine-Dalgarno duplex formation. Our work demonstrates that species-specific differences in the dimerization interface govern the overall conformation of the 100S ribosome particle and that for Thermus thermophilus no ribosome-ribosome interactions are involved in the interface.


Do health assets have a protective effect for hospitalized frail older adults?
Although increasing frailty is predictive of increased mortality and length of stay for hospitalized older adults, this approach ignores health assets that individuals can utilize to recover following hospital admission. To examine whether health assets mitigate the effect of frailty on outcomes for older adults admitted to hospital. Patients of 1418 aged ≥ 70 years admitted to 11 hospitals in Australia were evaluated at admission using the interRAI assessment system for Acute Care, which surveys a large number of domains, including cognition, communication, mood and behaviour, activities of daily living, continence, nutrition, skin condition, falls and medical diagnosis. The data set was interrogated for potential health assets and a multiple logistic regression adjusted for frailty index, age and gender as covariates was performed for the outcomes mortality, length of stay, re-admission and new need for residential care. Inpatient mortality was 3% and 4.5% of patients died within 28 days of discharge. Median length of stay was 7 days (IQR 4-11). In multivariate analysis that includes frailty, being able to walk further [OR 0.08 (0.01-0.63)], ability to leave the house [OR 0.35 (0.17-0.74)] and living alone [OR 0.28 (0.10-0.79)] were protective against mortality. The presence of a support person was associated with a decreased length of stay [OR 0.14 (0.08-0.25)]. The inclusion of health assets in predictive models can improve prognostication and highlights potential interventions to improve outcomes for hospitalized older adults.


The ins and outs of MYC regulation by posttranslational mechanisms.
The proteins of the MYC family are key regulators of cell behavior. MYC, originally identified as an oncoprotein, affects growth, proliferation, differentiation, and apoptosis of cells through its ability to regulate a significant number of genes. In addition MYC governs events associated with tumor progression, including genetic stability, migration, and angiogenesis. The pleiotropic activities attributed to MYC and their balanced control requires that the expression and function of MYC is tightly controlled. Indeed many different pathways and factors have been identified that impinge on MYC gene expression and protein function. In particular the protein is subject to different posttranslational modifications, including phosphorylation, ubiquitinylation, and acetylation. Here we discuss the latest developments regarding these modifications that control various aspects of MYC function, including its stability, the interaction with partner proteins, and the transcriptional potential.


Prostaglandin Reductase 1 as a Potential Therapeutic Target for Cancer Therapy.
Altered tumor metabolism is a hallmark of cancer and targeting tumor metabolism has been considered as an attractive strategy for cancer therapy. Prostaglandin Reductase 1 (PTGR1) is a rate-limiting enzyme involved in the arachidonic acid metabolism pathway and mainly responsible for the deactivation of some eicosanoids, including prostaglandins and leukotriene B4. A growing evidence suggested that PTGR1 plays a significant role in cancer and has emerged as a novel target for cancer therapeutics. In this review, we summarize the progress made in recent years toward the understanding of PTGR1 function and structure, highlight the roles of PTGR1 in cancer, and describe potential inhibitors of PTGR1. Finally, we provide some thoughts on future directions that might facilitate the PTGR1 research and therapeutics development.


Efficient synthesis of exomethylene- and keto-exomethylene-d-glucopyranosyl nucleoside analogs as potential cytotoxic agents.
A novel series of exomethylene- and keto-exomethylene-d-glucopyranonucleosides with thymine, uracil, and 5-fluorouracil as heterocyclic bases have been designed and synthesized. Wittig condensation of the 3-keto glucoside 1 gave the corresponding 1,2:5,6-di-O-isopropylidene-3-deoxy-3-methylene-d-glucofuranose (2), which after hydrolysis and acetylation led to the precursor 1,2,4,6-tetra-O-acetyl-3-deoxy-3-methylene-d-glucopyranose (4). Compound 4 was condensed with silylated thymine, uracil, and 5-fluorouracil, respectively, deacetylated and acetalated to afford 1-(3'-deoxy-4',6'-O-isopropylidene-3'-methylene-β-d-glucopyranosyl)pyrimidines 7a-c. Oxidation of the free hydroxyl group in the 2'-position of the sugar moiety led to the formation of the labile 1-(3'-deoxy-4',6'-O-isopropylidene-3'-methylene-β-d-glucopyranosyl-2'-ulose)pyrimidines 8a-c. Finally, deisopropylidenation of the resulted derivatives 8a-c afforded the diol nucleosides 9a-c. The target keto-exomethylene analogs 9a-c were more cytostatic against a variety of tumor cell lines than the corresponding saturated-hydroxy-exomethylene derivatives 6. In particular, the 5-fluorouracil derivative 9c was highly cytostatic at an IC(50) (50% inhibitory concentration) ranging between 0.56 and 9.4 microg/mL, which was comparable to the free parental 5-fluorouracil base.


The 5-HT1A receptor full agonist, 8-OH-DPAT inhibits ACTH-induced 5-HT2A receptor hyperfunction in rats: involvement of 5-HT1A receptors in the DOI-induced wet-dog shakes in ACTH-treated rats.
We examined the influence of 8-hydroxy-2-di-n-propylamino tetralin (8-OH-DPAT), a serotonin 1A (5-HT1A) receptor full agonist, on the wet-dog shake response induced by the (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT2A receptor agonist, in adrenocorticotropic hormone (ACTH)-treated rats. Chronic ACTH (100 microg/rat, s.c.) treatment for 14 d increased the wet-dog shake response induced DOI. The 8-OH-DPAT inhibited the wet-dog shake response induced by DOI in rats with ACTH for 14 d. On the other hand, the 8-OH-DPAT-induced hypothermia and flat body posture were inhibited when ACTH was administered for 14 d. These findings suggest that chronic treatment with ACTH decreased the sensitivity of the 5-HT1A receptor system; however, the inhibitory effects from the 5-HT1A receptors to the 5-HT2A receptor system is not inhibited in ACTH-treated rats.


Novel quinazolinone MJ-29 triggers endoplasmic reticulum stress and intrinsic apoptosis in murine leukemia WEHI-3 cells and inhibits leukemic mice.
The present study was to explore the biological responses of the newly compound, MJ-29 in murine myelomonocytic leukemia WEHI-3 cells in vitro and in vivo fates. We focused on the in vitro effects of MJ-29 on ER stress and mitochondria-dependent apoptotic death in WEHI-3 cells, and to hypothesize that MJ-29 might fully impair the orthotopic leukemic mice. Our results indicated that a concentration-dependent decrease of cell viability was shown in MJ-29-treated cells. DNA content was examined utilizing flow cytometry, whereas apoptotic populations were determined using annexin V/PI, DAPI staining and TUNEL assay. Increasing vital factors of mitochondrial dysfunction by MJ-29 were further investigated. Thus, MJ-29-provaked apoptosis of WEHI-3 cells is mediated through the intrinsic pathway. Importantly, intracellular Ca(2+) release and ER stress-associated signaling also contributed to MJ-29-triggered cell apoptosis. We found that MJ-29 stimulated the protein levels of calpain 1, CHOP and p-eIF2α pathways in WEHI-3 cells. In in vivo experiments, intraperitoneal administration of MJ-29 significantly improved the total survival rate, enhanced body weight and attenuated enlarged spleen and liver tissues in leukemic mice. The infiltration of immature myeloblastic cells into splenic red pulp was reduced in MJ-29-treated leukemic mice. Moreover, MJ-29 increased the differentiations of T and B cells but decreased that of macrophages and monocytes. Additionally, MJ-29-stimulated immune responses might be involved in anti-leukemic activity in vivo. Based on these observations, MJ-29 suppresses WEHI-3 cells in vitro and in vivo, and it is proposed that this potent and selective agent could be a new chemotherapeutic candidate for anti-leukemia in the future.


PGC-1α induced mitochondrial biogenesis in stromal cells underpins mitochondrial transfer to melanoma.
Progress in the knowledge of metabolic interactions between cancer and its microenvironment is ongoing and may lead to novel therapeutic approaches. Until recently, melanoma was considered a glycolytic tumour due to mutations in mitochondrial-DNA, however, these malignant cells can regain OXPHOS capacity via the transfer of mitochondrial-DNA, a process that supports their proliferation in-vitro and in-vivo. Here we study how melanoma cells acquire mitochondria and how this process is facilitated from the tumour microenvironment. Primary melanoma cells, and MSCs derived from patients were obtained. Genes' expression and DNA quantification was analysed using Real-time PCR. MSC migration, melanoma proliferation and tumour volume, in a xenograft subcutaneous mouse model, were monitored through bioluminescent live animal imaging. Human melanoma cells attract bone marrow-derived stromal cells (MSCs) to the primary tumour site where they stimulate mitochondrial biogenesis in the MSCs through upregulation of PGC1a. Mitochondria are transferred to the melanoma cells via direct contact with the MSCs. Moreover, inhibition of MSC-derived PGC1a was able to prevent mitochondrial transfer and improve NSG melanoma mouse tumour burden. MSC mitochondrial biogenesis stimulated by melanoma cells is prerequisite for mitochondrial transfer and subsequent tumour growth, where targeting this pathway may provide an effective novel therapeutic approach in melanoma.


Pediatric safety: review of the susceptibility of children with disabilities to injuries involving movement related events.
Toy-related injuries have increased significantly in the past decade, in particular those related to ride-on toys. This increase has been attributed to movement related events such as falls and inertial impacts. Furthermore, children with disabilities have been reported to be at a greater risk of being injured, and are therefore more susceptible to toy-related injuries. Although, efforts are being made to modify ride-on toys as a method for increasing quality of life in children with disabilities, there are very limited pediatric safety studies regarding children with disabilities and modified ride-on toys. This manuscript presents a systematic review of literature summarizing the current state of toy-related injuries including children with and without disabilities. Children exposed to inertial impacts in motor vehicle crashes have also been reviewed to present current pediatric safety testing methodologies and injury tolerance thresholds. Out of 2608 articles, 10 studies were included regarding current trends in toy-related injuries and safety testing methodologies. From this study, a gap in the literature was discovered concerning the susceptibility of children with disabilities to toy-related injuries, specifically in relation to ride-on toys and the repercussion surrounding such injuries. It is theorized that such lack of data is due to the difficulty and costs associated with experimental validation. Hence, it is recommended that computer simulations be used to provide preliminary data analysis.


Water-Resistant Subwavelength Perovskite Lasing from Transparent Silica-Based Nanocavity.
Great research efforts are devoted to exploring the miniaturization of chip-scale coherent light sources possessing excellent lasing performance. Despite the indispensable role in Si photonics, SiO2 is generally considered not contributing to the starting up and operation of integrated lasers. Here, this work demonstrates an extraordinary-performance subwavelength-scale perovskite vertical cavity laser with all-transparent SiO2 cavity, whose cavity is ultra-simple and composed of only two parallel SiO2 plates. By introducing a ligand-assisted thermally co-evaporation strategy, highly luminescent perovskite film with high reproducibility and excellent optical gain is grown directly on SiO2 . Benefitting from their high-refractive-index contrast, low-threshold, high-quality factor, and single-mode lasing is achieved in subwavelength range of ≈120 nm, and verified by long-range coherence distance (115.6 µm) and high linear polarization degree (82%). More importantly, the subwavelength perovskite laser device could operate in water for 20 days without any observable degradation, exhibiting ultra-stable water-resistant performance. These findings would provide a simple but robust and reliable strategy for the miniaturized on-chip lasers compatible with Si photonics.


Parasite-mediated manipulation? Toxoplasma gondii infection increases risk behaviour towards culling in red deer.
Parasites can modify host behaviour to increase their chances of survival and transmission. Toxoplasma gondii is a globally distributed protozoan whose ability to modify host behaviour is well known in taxa such as rats and humans. Less well known are the effects on the behaviour of wild species, with the exception of a few studies on primates and carnivores. Taking advantage of a culling activity conducted in Stelvio National Park (Italy), the serological status of T. gondii was studied in 260 individuals of red deer Cervus elaphus with respect to the risk of being culled. A temporal culling rank index was fitted as a response variable, and T. gondii serological status as the main explanatory variable in linear models, accounting for covariates such as sex, age, jaw length, bone marrow fat and culling location. The overall seroprevalence of T. gondii was 31.5%, and the selected models suggested that seropositive deer were culled earlier than seronegative ones, but this effect was only evident in females, in individuals with medium-good body condition, and in areas with greater human presence. Our results suggest that T. gondii may be involved in risk behaviour in large herbivores, supporting its role as a facilitator of predation risk.


A new sampling algorithm demonstrates that ultrasound equipment cleanliness can be improved.
Australia has established guidelines on cleaning for reusable ultrasound probes and accompanying equipment. This is a preliminary study investigating cleanliness standards of patient-ready ultrasound equipment in 5 separate health care facilities within a major city. The cleanliness was assessed using rapid adenosine triphosphate (ATP) testing used with a sampling algorithm which mitigates variability normally associated with ATP testing. Each surface was initially sampled in duplicate for relative light units (RLUs) and checked for compliance with literature recommended levels of cleanliness (<100 RLUs). Triplicate sampling was undertaken where necessary. A cleaning intervention step (CIS) followed using a disposable detergent wipe, and the surface was retested for ATP. There were 253 surfaces tested from the 5 health care facilities with 26% (66/253) demonstrating either equivocal or apparent lack of cleanliness. The CIS was conducted on 148 surfaces and demonstrated that for >91% (135/148) of surfaces, the cleaning standards could be improved significantly (P > .001). For 6% (9/148) of devices and surfaces, the CIS needed to be repeated at least once to achieve the intended level of cleanliness (<25 RLUs). This study indicates that ATP testing is an effective, real-time, quality assurance tool for cleanliness monitoring of ultrasound probes and associated equipment.


Effects of lipopeptide biosurfactants on clinical strains of Malassezia furfur growth and biofilm formation.
Lipopeptide biosurfactants (LBs) are biological molecules with low toxicity that have aroused growing interest in the pharmaceutical industry. Their chemical structure confers antimicrobial and antibiofilm properties against different species. Despite their potential, few studies have demonstrated their capability against Malassezia spp., commensal yeasts which can cause dermatitis and serious infections. Thus, the aim of this study was to evaluate the antifungal activity of biosurfactants produced by new strains of Bacillus subtilis TIM10 and B. vallismortis TIM68 against M. furfur and their potential for removal and inhibition of yeast biofilms. Biosurfactants were classified as lipopeptides by FTIR, and their composition was characterized by ESI-Q-TOF/MS, showing ions for iturin, fengycin, and surfactin, with a greater abundance of surfactin. Through the broth microdilution method, both biosurfactants inhibited the growth of clinical M. furfur strains. Biosurfactant TIM10 showed greater capacity for growth inhibition, with no statistical difference compared to those obtained by the commercial antifungal fluconazole for M. furfur 153DR5 and 154DR8 strains. At minimal inhibitory concentrations (MIC-2), TIM10 and TIM68 were able to inhibit biofilm formation, especially TIM10, with an inhibition rate of approximately 90%. In addition, both biosurfactants were able to remove pre-formed biofilm. Both biosurfactants showed no toxicity against murine fibroblasts, even at concentrations above MIC-2. Our results show the effectiveness of LBs in controlling the growth and biofilm formation of M. furfur clinical strains and highlight the potential of these agents to compose new formulations for the treatment of these fungi.


The sonographic appearances of gastric lymphoma.
The sonographic images obtained from 17 patients with gastric lymphoma were reviewed. In 15/17 cases the tumor presented as an abdominal mass, either with a "target-like" pattern or with a solid, homogeneous structure; in the remaining two cases only thickening of portions of the gastric wall was seen. Two features that may help to differentiate lymphoma from other gastric diseases were observed in patients of this series. In eight cases thickened mucosal folds could be identified within the gastric mass, outlined by strong luminal echoes arranged like the spokes of a wheel. A hypoechoic appearance of hte infiltrated gastric wall was seen in 13/17 cases; it was less echogenic than the adjacent liver parenchyma and, often, it was almost echo-free. Sonography is often used as the first imaging method in cases of patients with abdominal complaints and clinically unsuspected tumors of the stomach may be visualized first by it. In such cases, identification of these features within a gastric mass may allow sonography to suggest the lymphomatous nature of the disease.


Integrated approach to teaching and testing in histology with real and virtual imaging.
The University of Iowa College of Medicine histology teaching laboratory incorporates extensive Web- and computer-based teaching modalities, including the Virtual Microscope (VM), as emerging learning aids in histology and pathology laboratory instruction. We report here our experience in offering a multiple resource-based approach to laboratory instruction while retaining the opportunity and requirement of examining actual microscopic slide preparations with the microscope. Acceptance of this approach has been high among our students and faculty, and performance levels established over years of teaching histology by traditional means have been maintained.


The effectiveness of early treatment in segmental vitiligo: retrospective study according to disease duration.
Segmental vitiligo (SV) is usually characterized by a unilateral-dermatomal distribution, earlier onset and rapid progression followed by stabilization. The response to phototherapy in patients with SV is limited. We evaluated the treatment response in 39 cases of SV according to disease duration. Ten cases (50.0%) of Group 1 (duration ≤ 5 months) and five cases (26.3%) of Group 2 (duration > 5 months) showed more than 50% repigmentation. Contrary to previous reports, patients in our study responded well to medical treatments like oral steroids, topical calcineurin inhibitors and phototherapy when treated early after onset. The results suggest that early treatment is important.


Vasodilatory Effects of Combined Traditional Chinese Medicinal Herbs in Optimized Ratio.
Recently, a new syndromic disease combination theory of traditional Chinese medicine (TCM) for hypertensive treatment has been introduced. In the wake of this new concept, a new science-based TCM formula that counteracts various syndromes is needed. The objective of this study was to develop such a formula. Five of the most clinically prescribed TCM herbs that work on different syndromes, namely Gastrodia elata, Uncaria rhynchophylla, Pueraria thomsonii, Panax notoginseng, and Alisma orientale, were selected for this study. The fingerprints of these five herbs were analyzed by tri-step Fourier transform infrared spectroscopy. Three different solvents, 95% ethanol, 50% ethanol, and distilled water, were used for the maceration of the herbs and their vasodilatory effects were studied using in vitro precontracted aortic ring model. Among these, the 50% ethanolic extracts of G. elata (GE50) and A. orientale (AO50), and 95% ethanolic extracts of U. rhynchophylla (UR95), P. thomsonii (PT95), and P. notoginseng (PN95) were found to be the most effective for eliciting vasodilation. Thus, these five extracts were used for orthogonal stimulus-response compatibility group studies by using L25 (55) formula. The best combination ratio for GE50, UR95, PT95, PN95, and AO50, which was assigned as Formula 1 (F1), was found at EC0, EC25, EC20, EC20, and EC10, respectively. The vasodilatory effect of the extracts prepared from different extraction methods using F1 ratio was also studied. From the results, the EC50 and Rmax of total 50% ethanolic extract of five herbs using F1 ratio (F1-2) were 0.028 ± 0.005 mg/mL and 101.71% ± 3.64%, with better values than F1 (0.104 ± 0.014 mg/mL and 97.80% ± 3.12%, respectively). In conclusion, the optimum ratio and appropriate extraction method (F1-2) for the new TCM formula were revealed.


High levels of expression of a minigene version of the human pro alpha 1 (I) collagen gene in stably transfected mouse fibroblasts. Effects of deleting putative regulatory sequences in the first intron.
A minigene version of the human gene for the pro alpha(I) chain of type I procollagen (COL1A1) was prepared that contained -2.3 kilobases of the 5'-flanking sequence, the first 5 exons and introns, the last 6 exons and introns, and about 2 kilobases of the 3'-flanking sequence. The gene was then used for stable transfection experiments with mouse NIH 3T3 fibroblasts. Because the products of the minigene were shorter, it was possible to compare expression of the minigene with expression of the endogenous pro alpha 1 (I) gene by Northern and Western blot analyses. The results demonstrated that the construct contained enough of the gene to obtain high levels of expression in many of the stably transfected cells. Since previous observations suggested that the first intron of the pro alpha 1 (I) gene contained important cis-regulatory elements, two versions of the minigene were prepared in which most of the first intron was deleted. Comparison of expression of the minigene with expression of two deleted versions of the same gene established that 85% of the total sequences in the first intron are not essential for high levels of expression of the gene in stably transfected mouse fibroblasts.


Model-free forecasting outperforms the correct mechanistic model for simulated and experimental data.
Accurate predictions of species abundance remain one of the most vexing challenges in ecology. This observation is perhaps unsurprising, because population dynamics are often strongly forced and highly nonlinear. Recently, however, numerous statistical techniques have been proposed for fitting highly parameterized mechanistic models to complex time series, potentially providing the machinery necessary for generating useful predictions. Alternatively, there is a wide variety of comparatively simple model-free forecasting methods that could be used to predict abundance. Here we pose a rather conservative challenge and ask whether a correctly specified mechanistic model, fit with commonly used statistical techniques, can provide better forecasts than simple model-free methods for ecological systems with noisy nonlinear dynamics. Using four different control models and seven experimental time series of flour beetles, we found that Markov chain Monte Carlo procedures for fitting mechanistic models often converged on best-fit parameterizations far different from the known parameters. As a result, the correctly specified models provided inaccurate forecasts and incorrect inferences. In contrast, a model-free method based on state-space reconstruction gave the most accurate short-term forecasts, even while using only a single time series from the multivariate system. Considering the recent push for ecosystem-based management and the increasing call for ecological predictions, our results suggest that a flexible model-free approach may be the most promising way forward.


Aplanatic double reflection system for thermophotovoltaic applications: design.
The design of a solar concentrator is presented; it consists of a spherical mirror and a field of Fresnel mirror facets deployed on a spherical surface so that sine condition is satisfied, eliminating both spherical aberration and coma. This particular easy to construct optical system yields high concentration ratios and has the distinct advantage of having a narrow beam aperture near the receiver. These design features make the concentrator particularly suitable for thermophotovoltaic applications.


Factors associated with risk sexual behaviours of HIV/STDs infection among university students in Henan, China: a cross-sectional study.
This study aimed to identify factors associated with risk sexual behaviours and target high-risk groups at risk of HIV/STDs infection among university students. The cross-sectional study was conducted from 1 November to 31 December 2020 in one university, located in Henan Province. A total of 1602 individuals who reported having ever had sex were analyzed as the subjects of this study. Descriptive analysis and multivariable logistic regression analysis were applied for this study to assess factors associated with risk sexual behaviours among university students. University students who reported having ever had sex accounted for about 9%, with an average age of 19.37 ± 1.03. Of them, having multiple sexual partners and inconsistent condom use during the last 6 months were 37.3% and 35%, respectively. Over 50% of participants had their sexual debut before the age of 18. Bisexual students (AOR = 0.27; 95% CI 0.16, 0.44) and those who lived on over 3000 Yuan per month (AOR = 0.50; 95% CI 0.28, 0.91) were consistently less likely to engage in condom use during the last 6 months. University students who were from high-grade (AOR = 1.56; 95% CI 1.12, 2.18 for sophomore; AOR = 1.84; 95% CI 1.28, 2.65 for junior; AOR = 2.07; 95% CI 1.38, 3.11 for senior), who lived on over 3,000 Yuan per month (AOR = 4.19; 95% CI 2.17, 8.11) or who reported being homosexual (AOR = 3.92; 95% CI 2.17, 7.06) and bisexual (AOR = 33.22; 95% CI 13.11, 84.15) were more likely to have multiple sexual relationships. University students who had sexual debut before the age of 18 were more likely to engage in risk sexual behaviours. The prevalence of sexual activity among Chinese university students is generally low, but risk sexual behaviours are of considerable concern. University students with higher living expenses, who are not heterosexual and who are younger at first sexual intercourse tend to engage in risk sexual behaviours. The scale-up of intervention is the need to prevent the expansion of the HIV epidemic among young students.


Increased prescribing trends of paediatric psychotropic medications.
Psychotropic medication use by children in the USA has increased. We used the IMS MIDAS Prescribing Insights to examine prescribing trends in nine countries between the years 2000 and 2002. Trends in seven countries rose significantly from year 2000 to 2002; the UK had the highest increase (68%).


Ovarian cancer epidemiology in the era of collaborative team science.
Over the past decade, a number of consortia have formed to further investigate genetic associations, pathogenesis, and epidemiologic risk and prognostic factors for ovarian cancer. Here, we review the benefits that ovarian cancer consortia provide as well as challenges that have arisen. Methods for managing key challenges are also discussed. We review the structural organization and some of the milestone epidemiologic publications of five consortia dedicated to the study of ovarian cancer, including the Ovarian Cancer Association Consortium (OCAC), the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Ovarian Cancer Cohort Consortium (OC3), the Collaborative Group on Epidemiological Studies of Ovarian Cancer (The Oxford Collaborative Group), and the Ovarian Cancer in Women of African Ancestry (OCWAA) consortium. As ovarian cancer is a rare and heterogeneous disease, consortia have made important contributions in the study of risk factors by improving statistical power beyond what any single study, or even a few studies, would provide. Thus, a major accomplishment of consortial research is enhanced characterization of histotype-specific risk factor associations. In addition, consortia have facilitated impressive synergy between researchers across many institutions, spawning new collaborative research. Importantly, through these efforts, many challenges have been met, including difficulties with data harmonization and analysis, laying a road map for future collaborations. While ovarian cancer consortia have made valuable contributions to the ovarian cancer epidemiological literature over the past decade, additional efforts comprising of new, well-designed case-control studies are needed to further elucidate novel, histotype-specific risk, and prognostic factors which are not consistently available in existing studies.


Inherent Fluorescence Demonstrates Immunotropic Properties for Novel Janus Kinase 3 Inhibitors.
There is a general question in small molecule pharmacology about how apparent compound concentrations in blood, plasma, and organs actually relate to actual amounts at the target site of a compound. In this study, we used inherently fluorescent JAK3 ligands and their macrolide conjugates to investigate the relationship between physical properties, apparent bulk concentration, and organ and subcellular distribution. In vitro uptake into immune cells suggested that much of the substance was associated with granules or organelles. Samples from murine pharmacokinetic studies were analyzed by both conventional mass spectrometry and cryofluorescence microscopy methods to show the distribution of a compound within organs and cells without artifacts of fixation. These observations confirm the uptake of granules observed in vitro. Data from macrolides carrying either a coumarin fluorophore or a JAK3 inhibitor were similar, suggesting that the distribution is directed by the properties of the larger macrolide. These data show a propensity for azalide macrolides to concentrate in the lung and gut epithelia and suggest that the plasma- or whole-blood-derived estimates of drug levels almost certainly underestimate concentrations of macrolides in the mucous membranes. Thus, their apparent efficacy at sub-bacteriostatic doses may reflect their higher levels in barrier layers.


[DIFFICULTIES IN DISSECTION OF URINARY BLADDER IN TOTAL LAPAROSCOPIC HYSTERECTOMY.]
The dissection of urinary bladder is a crucial phase of the laparoscopic operation of hysterectomy. The latter dissection may become even more difficult in the context of history of operative interventions as cesarean section or cervical conization, presence of cervical or isthmic myomatous nodes, as well as upon a bad operative technique. The obeying of some basic principles (knowledge of pelvic anatomy and topographic interrelations; considering of present risk factors; intraoperative screening for complications and their early treatment) results in the optimal performance of laparoscopic hysterectomy.


Understanding the causes and consequences of injuries to adolescents growing up in poverty in Ethiopia, Andhra Pradesh (India), Vietnam and Peru: a mixed method study.
The World Health Organization estimates that almost half of all premature deaths among 15- to 19-year olds can be attributed to injuries with most (95%) fatal injuries occurring in low- and middle-income countries. Yet the evidence base for adolescent injuries in low-income countries is poor. This article uses a mixed method approach to gain an understanding of patterns, causes and consequences of unintentional injuries among adolescents aged between 14 and 16 years in four low-income country settings. Survey data collected in 2009 in Ethiopia, India (Andhra Pradesh), Peru and Vietnam (from ~900 adolescents in each country) were integrated with qualitative research (conducted between 2007 and 2011) with a nested sample of older cohort children in Ethiopia (n = 25) and India (n = 25) using an iterative process. Logistic regression models were fitted to examine potential risk factors for injuries. Injuries were a concern for adolescents in all countries and occurred during work, recreation and sports or transportation. Being male was associated with an increased risk for all types of injuries, whereas being poor was only significantly associated with work injuries. Area of residence (urban vs rural) made a difference in some countries and for some kinds of injuries as did perceived health status. Qualitative findings highlight the consequences of injuries not only for the adolescents but also for the social and economic status of the entire household. Injury prevention programmes need to be specific to cultural and environmental settings, expectations of adolescent's responsibilities and responsive to the context of poverty.


Association of adipokines, interleukin-6, and tumor necrosis factor-α concentrations with clinical characteristics and presence of spinal syndesmophytes in patients with ankylosing spondylitis: A cross-sectional study.
Objective To identify correlations of the serum leptin, adiponectin, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) concentrations with the clinical characteristics, presence of spinal syndesmophytes, and body composition in patients with ankylosing spondylitis (AS). Methods Forty-eight patients with AS were compared with 41 sex- and age-matched controls. Assessment included clinical characteristics and the presence of spinal syndesmophytes. The serum leptin, adiponectin, TNF-α, and IL-6 concentrations were determined. Body composition was evaluated using dual-energy X-ray absorptiometry. Results Patients with AS and controls had similar fat mass and lean mass. Patients with AS had higher serum TNF-α and leptin concentrations than controls (52.3 vs. 1.5 pg/mL and 17.2 vs. 9.0 µg/mL, respectively). The IL-6 and adiponectin concentrations were not significantly different between the two groups. Patients with syndesmophytes had higher leptin concentrations than those without syndesmophytes (22.1 vs. 10.9 µg/mL); this difference remained after adjustment for the body mass index. Conclusion Elevated leptin concentrations are associated with spinal radiographic damage in patients with AS and can serve as a biomarker. Future studies should evaluate whether leptin might be a potential target for treatments to avoid structural damage.


Integrative approach reveals a new species of Nematocharax (Teleostei: Characidae).
An integrative approach based on morphological and multilocus genetic data was used to describe a new species of Nematocharax from the headwaters of the upper Contas River on the Diamantina Plateau, north-eastern Brazil and to infer the relationships among evolutionary lineages within this fish genus. Multispecies coalescent inference using three mitochondrial and five nuclear loci strongly supports a basal split between Nematocharax venustus and the new species, whose distinctive morphological characters include absence of filamentous rays on pelvic fins of maturing and mature males, reduced anal-fin lobe length and lower body depth. The unique morphological and genetic traits of the population from the upper Contas River were supported by previous reports based on cytogenetics, DNA barcode and geometric morphometrics, reinforcing the validation of the new species. The conservation status of this new species is discussed.


A strategic action plan for achieving uncompromising "treat to target" in individuals with insulin-dependent diabetes: a report by the Center for Insulin-Dependent Diabetes Access' Blue Ribbon Panel.
The Center for Insulin-Dependent Diabetes Access, created by the Juvenile Diabetes Research Foundation International and funded by an unrestricted grant from The Medtronic Foundation, convened a Blue Ribbon Panel (the Panel) to identify barriers to achieving universal treatment-to-target in patients with insulin-dependent diabetes and to recommend solutions for addressing those barriers. The Panel was comprised of experts in diabetes care and included providers, academicians, researchers, payers, patient advocates, and policymakers. After reviewing the latest research on diabetes care, the Panel made six overall findings that identify barriers to achieving optimal diabetes care and made recommendations to address those barriers that are intended to achieve the goal of universal, uncompromising "Treat to Target" in insulin-dependent patients. The Panel's findings were: Finding 1: Improving care of patients with insulin-dependent diabetes depends on the public availability and ongoing collection of data that document patient characteristics, processes of care, health outcomes, the benefits and costs of new technologies, and the benefits and costs of different care models. Finding 2: Availability of new technologies and information systems for monitoring and treating insulin-dependent diabetes is critical to achieving recommended hemoglobin A1c levels. Finding 3: Increased reimbursement for new technologies and services provided by the "team" approach to medical management, such as coordinated non-face-to-face care and Internet communications, is imperative to achieving optimal diabetes care. Finding 4: Improving access to endocrinologists, certified diabetes educators, and adopting a chronic care or "team" approach to treating insulin-dependent diabetes are critical to achieving a "Treat to Target" objective. Finding 5: Primary care providers and individuals with insulin-dependent diabetes need to better understand the importance and impact of intensive insulin management and the "team" approach for treating diabetes in improving quality of life and reducing the incidence of long-term diabetes-related complications. Finding 6: Demographic characteristics of individuals with insulin-dependent diabetes require innovative approaches to patient education, outreach, and patient-centric care in order to achieve a "Treat to Target" objective. In the detailed report that follows, each finding is accompanied by a series of recommended action items intended to address the barriers that the Panel identified. A number of entities and organizations have ongoing and planned activities intended to improve diabetes care, particularly for individuals with insulin-dependent diabetes. The Panel recommended that the diabetes community work to coordinate those efforts in order to avoid duplication and ensure more effective program management of those activities.


Reference as an Interactive Achievement: Sequential and Longitudinal Analyses of Labeling Interactions in Shared Book Reading and Free Play.
The present study examines how young children and their caregivers establish reference by jointly developing stable patterns of bodily, perceptual, and interactive coordination. Our longitudinal investigation focuses on two mother-child dyads engaged in picture-book reading and play. The dyads were videotaped at home once every 6 weeks while the children aged from 9 to 24 months. Inspired by conversation analysis and multimodal analysis, our developmental approach builds on the insight that the situated and embodied production of reference is fundamentally an interactive achievement. To examine the acquisition of reference, we developed a descriptive instrument that takes account of not only the dyad's joint accomplishment but also each participant's contributions to it. The instrument is based on the sequential reconstruction of the jobs that both participants have to accomplish jointly in order to achieve reference: establishing visual perception as a relevant resource, constituting a domain of scrutiny, locating a target, and construing the (meaning of the) referent. Methodologically, these jobs serve as a tertium comparationis for the longitudinal comparison of both the adult's as well as the child's contributions to establishing reference. We used this instrument to examine (1) what bodily and verbal resources the participants employed, and (2) how their contributions to accomplishing the jobs changed over time. Findings showed that the acquisition of reference was closely related to the child's increasing ability to recognize, fulfill, and set up conditional relevancies. We conclude that the adult's dynamic and contextualized use of conditional relevancies, recipient design, and observability is a crucial driving force in the acquisition of reference.


Vaporization-condensation-recrystallization process-mediated synthesis of helical m-aminobenzoic acid nanobelts.
One-dimensional (1D) helical organic nanostructures were synthesized by a modified vapor-solid (VS) process, called the vaporization-condensation-recrystallization (VCR) process. The conventional solution-phase synthetic methods generally mediate self-assemblies of repeating unit molecules. To provide enough intermolecular interaction forces among the unit molecules, such strategy requires specific designs and syntheses of complex unit molecules as they possess numerous functional groups including phenyl rings, hydroxyl groups, long aliphatic chains, etc. On the contrary, we found that small and simple organic molecules, for example, m-ABA, could be self-assembled by the VCR process, resulting in 1D helical organic nanostructures. When m-aminobenzoic acid (m-ABA) powders were vaporized and transported to be condensed on a cooler region, the condensates were recrystallized into 1D helical nanobelts. Each step of the VCR process was confirmed from control experiments performed by varying reaction times, substrate types, and reaction temperatures. Powder XRD data, SAED analysis, and theoretical calculations revealed that dimers of m-ABA molecules have repeating units, and the growth axis of m-ABA nanohelices is [100].


Serum apelin is associated with affective disorders in peritoneal dialysis patients.
Depression and anxiety are prevalent affective disorders in peritoneal dialysis (PD) patients. Recent research has proposed a potential role of apelinergic system in pathogenesis of depression. The present study aimed to evaluate the frequency of depression and anxiety and their potential relation with serum apelin levels among PD patients. A total of 40 PD patients were enrolled into the study. Depressive symptoms and anxiety were assessed with the Beck's Depression Inventory and the Beck's Anxiety Inventory. Serum apelin-12 levels were measured by immunoenzymatic assays using commercially available ELISA kit for standard human apelin. Of the patients, 16 (40%) had depression, 20 (50%) had anxiety. The patients with depression and anxiety had a significantly longer time on dialysis (p < 0.001 for both), significantly higher serum apelin (p < 0.001 for both) and C-reactive protein levels (p < 0.001 for both) than those without depression and anxiety. In multivariate analysis, serum apelin was the only parameter associated independently with depression and anxiety scores. A substantial number of PD patients had depression and anxiety. Increased levels of serum apelin may constitute a significant independent predictor of development of depression and anxiety in PD patients.


Stereospecific Pd-Catalyzed Intermolecular C(sp(3))-C(sp) Cross-Coupling of Diarylmethyl Carbonates and Terminal Alkynes Under Base-Free Conditions.
A palladium-catalyzed intermolecular decarboxylative C(sp(3))-C(sp) coupling of diarylmethyl carbonates and terminal alkynes has been developed. The reaction proceeds smoothly under external base-free conditions to deliver the corresponding alkynylated diarylmethanes with the liberation of CO2 and MeOH as the sole byproducts. Moreover, enantioenriched diarylmethyl carbonates are stereospecifically converted to optically active cross-coupling products with inversion of configuration. Thus, the stereospecific palladium catalysis can provide new and unique access to the alkynylated chiral tertiary stereocenters, which are relatively difficult to construct by conventional methods.


Gene microarray assessment of multiple genes and signal pathways involved in androgen-dependent prostate cancer becoming androgen independent.
To study the gene expression change and possible signal pathway during androgen-dependent prostate cancer (ADPC) becoming androgen-independent prostate cancer (AIPC), an LNCaP cell model of AIPC was established using flutamide in combination with androgen-free environment inducement, and differential expression genes were screened by microarray. Then the biological process, molecular function and KEGG pathway of differential expression genes are analyzed by Molecule Annotation System (MAS). By comparison of 12,207 expression genes, 347 expression genes were acquired, of which 156 were up-ragulated and 191 down-regulated. After analyzing the biological process and molecule function of differential expression genes, these genes are found to play crucial roles in cell proliferation, differntiation, cell cycle control, protein metabolism and modification and other biological process, serve as signal molecules, enzymes, peptide hormones, cytokines, cytoskeletal proteins and adhesion molecules. The analysis of KEGG show that the relevant genes of AIPC transformation participate in glutathione metabolism, cell cycle, P53 signal pathway, cytochrome P450 metabolism, Hedgehog signal pathway, MAPK signal pathway, adipocytokines signal pathway, PPAR signal pathway, TGF-β signal pathway and JAK-STAT signal pathway. In conclusion, during the process of ADPC becoming AIPC, it is not only one specific gene or pathway, but multiple genes and pathways that change. The findings above lay the foundation for study of AIPC mechanism and development of AIPC targeting drugs.


Aortic annular sizing for transcatheter aortic valve replacement using cross-sectional 3-dimensional transesophageal echocardiography.
This study compared cross-sectional three-dimensional (3D) transesophageal echocardiography (TEE) to two-dimensional (2D) TEE as methods for predicting aortic regurgitation after transcatheter aortic valve replacement (TAVR). Data have shown that TAVR sizing using cross-sectional contrast computed tomography (CT) parameters is superior to 2D-TEE for the prediction of paravalvular aortic regurgitation (AR). Three-dimensional TEE can offer cross-sectional assessment of the aortic annulus but its role for TAVR sizing has been poorly elucidated. All patients had severe symptomatic aortic stenosis and were treated with balloon-expandable TAVR in a single center. Patients studied had both 2D-TEE and 3D imaging (contrast CT and/or 3D-TEE) of the aortic annulus at baseline. Receiver-operating characteristic curves were generated for each measurement parameter using post-TAVR paravalvular AR moderate or greater as the state variable. For the 256 patients studied, paravalvular AR moderate or greater occurred in 26 of 256 (10.2%) of patients. Prospectively recorded 2D-TEE measurements had a low discriminatory value (area under the curve = 0.52, 95% confidence interval: 0.40 to 0.63, p = 0.75). Average cross-sectional diameter by CT offered a high degree of discrimination (area under the curve = 0.82, 95% confidence interval: 0.73 to 0.90, p < 0.0001) and mean cross-sectional diameter by 3D-TEE was of intermediate value (area under the curve = 0.68, 95% confidence interval: 0.54 to 0.81, p = 0.036). Cross-sectional 3D echocardiographic sizing of the aortic annulus dimension offers discrimination of post-TAVR paravalvular AR that is significantly superior to that of 2D-TEE. Cross-sectional data should be sought from 3D-TEE if good CT data are unavailable for TAVR sizing.


Positive Childhood Experiences and Depression Among College Students During the COVID-19 Pandemic: A Moderated Mediation Model.
In light of the ongoing COVID-19 pandemic, mental health concerns have become more prevalent worldwide. However, there is a lack of research specifically addressing the mental well-being of college art students. Therefore, the purpose of this study is to examine the prevalence of depressive symptoms among college music students and explore the factors that predict and alleviate these symptoms amidst the challenges posed by the COVID-19 pandemic. An online survey was conducted among college music students (n = 407) from two universities at May 2022 in China. Self-report scales were used to measure levels of depression (Zung Self-Rating Depression Scale), positive childhood experiences (Benevolent Childhood Experiences Scale), social support (Multi-Dimensional Scale of Perceived Social Support), and regulatory emotional self-efficacy (Regulatory Emotional Self-Efficacy Scale). Hayes PROCESS macro for SPSS was used to test the hypothesized effects of regulatory emotional self-efficacy and social support in the relationship between positive childhood experiences and depression. Results showed that, the prevalence of depression symptoms of the current study sample was 64.13%, positive childhood experiences had a significant and negative predictive effect on the depression of college music students, and the relation was partially mediated by regulatory emotional self-efficacy. Furthermore, social support moderated the relationship between positive childhood experiences and regulatory emotional self-efficacy, the relation was significant only for students with higher levels of social support, social support may enhance and amplify the positive impacts of positive childhood experiences on regulatory emotional self-efficacy. The findings reveal a significant prevalence of depression among college music students during the COVID-19 epidemic, underscoring the seriousness of the issue. Moreover, this study contributes to a deeper comprehension of how positive childhood experiences alleviate depression among college music students. These insights hold potential for informing mental health education initiatives tailored to college art students in the post-pandemic era, offering valuable guidance for promoting their well-being and resilience.


Observations on the eosinophilic granules in the dorsal papillae of the dog tongue.
The granules from epithelium of filiform papillae of the dorsal surface of dog tongue were characterized as eosinophilic in contrast to the classically described basophilic keratohyalin granules which stain characteristically with hematoxylin. The eosinophilic granules also stained with Sakaguchi oxine reaction indicating the presence of arginine. At the ultrastructural level the round or oval granules varied in size and electron density. The granules were often associated with ribosomes and/or tonofilaments and were not limited by membranes. These granules disappeared in the superficial layers of epithelium which was parakeratotic in nature. Our studies indicate that the eosinophilic granules belong to the class of keratohyalin granules which are known to be heterogeneous in their morphology and biological composition.


Expression of Glial Cell Line-Derived Neurotrophic Factor (GDNF) and the GDNF Family Receptor Alpha Subunit 1 in the Paravaginal Ganglia of Nulliparous and Primiparous Rabbits.
To evaluate the expression of glial cell line-derived neurotrophic factor (GDNF) and its receptor, GDNF family receptor alpha subunit 1 (GFRα-1) in the pelvic (middle third) vagina and, particularly, in the paravaginal ganglia of nulliparous and primiparous rabbits. Chinchilla-breed female rabbits were used. Primiparas were killed on postpartum day 3 and nulliparas upon reaching a similar age. The vaginal tracts were processed for histological analyses or frozen for Western blot assays. We measured the ganglionic area, the Abercrombie-corrected number of paravaginal neurons, the cross-sectional area of the neuronal somata, and the number of satellite glial cells (SGCs) per neuron. The relative expression of both GDNF and GFRα-1 were assessed by Western blotting, and the immunostaining was semiquantitated. Unpaired two-tailed Student t -test or Wilcoxon test was used to identify statistically significant differences (P≤0.05) between the groups. Our findings demonstrated that the ganglionic area, neuronal soma size, Abercrombie-corrected number of neurons, and number of SGCs per neuron were similar in nulliparas and primiparas. The relative expression of both GDNF and GFRα-1 was similar. Immunostaining for both GDNF and GFRα-1 was observed in several vaginal layers, and no differences were detected regarding GDNF and GFRα-1 immunostaining between the 2 groups. In the paravaginal ganglia, the expression of GDNF was increased in neurons, while that of GFRα-1 was augmented in the SGCs of primiparous rabbits. The present findings suggest an ongoing regenerative process related to the recovery of neuronal soma size in the paravaginal ganglia, in which GDNF and GFRα-1 could be involved in cross-talk between neurons and SGCs.


Ligand and Redox Partner Binding Generates a New Conformational State in Cytochrome P450cam (CYP101A1).
It has become increasingly clear that cytochromes P450 can cycle back and forth between two extreme conformational states termed the closed and open states. In the well-studied cytochrome P450cam, the binding of its redox partner, putidaredoxin (Pdx), shifts P450cam toward the open state. Shifting to the open state is thought to be important in the formation of a proton relay network essential for O-O bond cleavage and formation of the active Fe(IV)═O intermediate. Another important intermediate is the oxy-P450cam complex when bound to Pdx. Trapping this intermediate in crystallo is challenging owing to its instability, but the CN- complex is both stable and an excellent mimic of the O2 complex. Here we present the P450cam-Pdx structure complexed with CN-. CN- results in large conformational changes including cis/trans isomerization of proline residues. Changes include large rearrangements of active-site residues and the formation of new active-site access channel that we have termed channel 2. The formation of channel 2 has also been observed in our previous molecular dynamics simulations wherein substrate binding to an allosteric site remote from the active site opens up channel 2. This new structure supports an extensive amount of previous work showing that distant regions of the structure are dynamically coupled and underscores the potentially important role that large conformational changes and dynamics play in P450 catalysis.


Lymphocyte transformation test with liver-specific protein and phytohaemagglutinin in patients with liver disease.
Lymphocytes from thirty-four untreated patients with various liver diseases were stimulated in a lymphocyte transformation test with liver-specific protein (LSP). Eight of ten patients with chronic active or persistent hepatitis, two of five patients with non-alcoholic cirrhosis and six of nineteen patients with acute hepatitis showed a positive in vitro reactivity to LSP. In a control group of twelve persons without evidence of liver disease, eleven gave a negative response to LSP stimulation, whereas one person showed a positive response. Among fourteen patients with chronic hepatitis or non-alcoholic cirrhosis treated with prednisone at the time of the investigation, only one showed reactivity to LSP stimulation. Three patients in this group had previously had a positive reaction before prednisone was given. There was no statistically significant correlation between the reactivity to LSP stimulation and the presence or absence of hepatitis-associated antigen (HBAg) in serum, or with the biochemical liver parameters. The response to in vitro stimulation with phytohaemagglutinin (PHA) was found to be significantly lower as compared with the control group in eleven patients with alcoholic liver disease and in the patients with acute hepatitis who had HBAg in serum. This decrease in reactivity could apparently not be ascribed to immuno-suppressive factors in the patients' sera.


Medicinal Plants Used in the Treatment of Mental and Neurological Disorders in Ghana.
Mental and neurological disorders are a serious public health challenge globally, particularly in developing countries where cultural factors and limited access to standard healthcare have led to a reliance on traditional medicines. However, ethnopharmacological characterization of traditional medicines used to treat these diseases is lacking. In this study, an ethnobotanical description of plant species used in treating mental and neurological disorders in Ghana and an update of their experimentally validated pharmacological relevance are provided. Two hundred herbalists agreed to participate but sixty-six specialized in treating mental and neurological disorders were interviewed on their traditional medical practice. Literature review was conducted to verify the experimentally validated pharmacological importance of the reported plants. Thirty-two plant species belonging to twenty-eight families were identified. Most plant species had either analgesic (50%), anxiolytic (18.8%), or anticonvulsant (15.6%) properties. Others had reported sedative, anti-Alzheimer's disease, motor coordination, antipsychotic, antidepressant, cognitive enhancement, and neuroprotective properties. While Ageratum conyzoides L. (Asteraceae) and Ocimum gratissimum L. (Lamiaceae) were the most commonly mentioned species with analgesic properties, Lantana camara L. (Verbenaceae) was the most-reported anxiolytic product, with Cymbopogon citratus DC. (Gramineae), Mangifera indica L., Tetrapleura tetraptera Schum Taub. (Fabaceae), and Persea Americana Mill (Lauraceae) being the most studied anticonvulsants. This study provides the first report specifically on medicinal plants used in treating mental and neurological disorders in Ghana. Most of the identified plants have been scientifically confirmed to possess neuro- and psychopharmacological properties and may serve as templates for drug development.


Population pharmacokinetics, brain distribution, and pharmacodynamics of 2nd generation dopamine transporter selective benztropine analogs developed as potential substitute therapeutics for treatment of cocaine abuse.
A second generation of N-substituted 3alpha-[bis(4'-fluorophenyl)methoxy]-tropanes (GA 1-69, JHW 005 and JHW 013) binds with high affinity to the dopamine transporter (DAT) and are highly selective toward DAT compared to muscarinic receptor binding (M1). The objective of this study was to characterize brain distribution, pharmacokinetics, and pharmacodynamics [extracellular brain dopamine (DA) levels] of three novel N-substituted benztropine (BZT) analogs in male Sprague-Dawley rats. The BZT analogs displayed a higher distribution (Vd = 8.69-34.3 vs. 0.9 L/kg) along with longer elimination (t l/2: 4.1-5.4 vs. 0.5 h) than previously reported for cocaine. Brain-to-plasma partition coefficients were 1.3-2.5 vs. 2.1 for cocaine. The effect of the BZT analogs on extracellular brain (DA) levels ranged from minimal effects (GA 1-69) to several fold elevation (approximately 850% of basal DA for JHW 013) at the highest dose evaluated. PK/PD analysis of exposure-response data resulted in lower IC50 values for the BZT analogs compared to cocaine indicating their higher potency to inhibit DA reuptake (0.1-0.3 vs. 0.7 mg/L). These BZT analogs possess significantly different PK and PD profiles as compared to cocaine suggesting that further evaluation as cocaine abuse therapeutics is warranted.


Effect of transplanting suprachiasmatic nuclei from donors of different ages into completely SCN lesioned hamsters.
The suprachiasmatic nucleus (SCN) is the primary circadian pacemaker in mammals. Ralph and colleagues /14/ provided recent new evidence for this by transplanting SCNs between golden hamsters with different genetically determined periods and producing circadian rhythms of running wheel activity with periods characteristic of the donor. We have extended these studies in order to evaluate the age range of donor tissue that can be used for transplantation. SCN of hamsters from embryonic day 11 through postnatal day 12 can serve as functional grafts to restore rhythmicity to arrhythmic SCN lesioned animals. The time between SCN transplantation and onset of rhythmicity does not depend on the age of the donor. The presence of patches containing vasoactive intestinal peptide (VIP) immunoreactive cells is a good indicator of graft success, while its absence is correlated with a lack of transplant effect. The 18 day span during which SCN tissue can be harvested for transplantation should expand the uses to which this technique can be put. Our results also suggest that it would be advantageous to examine the age range of neural tissue that can be used in other transplantation models.


Atomic force microscopy of red-light photoreceptors using peakforce quantitative nanomechanical property mapping.
Atomic force microscopy (AFM) uses a pyramidal tip attached to a cantilever to probe the force response of a surface. The deflections of the tip can be measured to ~10 pN by a laser and sectored detector, which can be converted to image topography. Amplitude modulation or "tapping mode" AFM involves the probe making intermittent contact with the surface while oscillating at its resonant frequency to produce an image. Used in conjunction with a fluid cell, tapping-mode AFM enables the imaging of biological macromolecules such as proteins in physiologically relevant conditions. Tapping-mode AFM requires manual tuning of the probe and frequent adjustments of a multitude of scanning parameters which can be challenging for inexperienced users. To obtain high-quality images, these adjustments are the most time consuming. PeakForce Quantitative Nanomechanical Property Mapping (PF-QNM) produces an image by measuring a force response curve for every point of contact with the sample. With ScanAsyst software, PF-QNM can be automated. This software adjusts the set-point, drive frequency, scan rate, gains, and other important scanning parameters automatically for a given sample. Not only does this process protect both fragile probes and samples, it significantly reduces the time required to obtain high resolution images. PF-QNM is compatible for AFM imaging in fluid; therefore, it has extensive application for imaging biologically relevant materials. The method presented in this paper describes the application of PF-QNM to obtain images of a bacterial red-light photoreceptor, RpBphP3 (P3), from photosynthetic R. palustris in its light-adapted state. Using this method, individual protein dimers of P3 and aggregates of dimers have been observed on a mica surface in the presence of an imaging buffer. With appropriate adjustments to surface and/or solution concentration, this method may be generally applied to other biologically relevant macromolecules and soft materials.


Hierarchical brain structural-functional coupling associated with cognitive impairments in mild traumatic brain injury.
Mild traumatic brain injury (mTBI) disrupts the integrity of white matter microstructure, which affects brain functional connectivity supporting cognitive function. Although the relationship between structural and functional connectivity (SC and FC), here called SC-FC coupling, has been studied on global level in brain disorders, the long-term disruption of SC-FC coupling in mTBI at regional scale was still unclear. The current study investigated the alteration pattern of regional SC-FC coupling in 104 acute mTBI patients (41 with 6-12 months of follow-up) and 56 healthy controls (HCs). SC and FC networks were constructed to measure regional, intra-network, and inter-network SC-FC coupling. Compared with HCs, acute mTBI exhibited altered SC-FC coupling of the sensorimotor network (SMN). The coupling laterality indicators of the SMN can identify mTBI from controls. The persistent SC-FC decoupling of the SMN and the additional decoupling of the default mode network (DMN) were observed in chronic mTBI. Crucially, decoupling of the SMN and DMN predicted better cognitive outcomes. The findings revealed the SC-FC coupling alternations exhibited hierarchical trend originating from the sensorimotor cortex to high-order cognitive regions with the progression of mTBI. The regional and hierarchical SC-FC coupling may be a prognostic biomarker to provide insights into the pathophysiology mechanism of mTBI.


Biliary manometry, bacterial characteristics, bile composition, and histologic changes fifteen to seventeen years after endoscopic sphincterotomy.
To evaluate the function of the biliary sphincter 15 to 17 years after endoscopic sphincterotomy and to investigate if loss of sphincter function is associated with bacterial colonization, changes in bile composition, or inflammation of the biliary system. Eight patients who had undergone endoscopic sphincterotomy for bile duct stones 15 to 17 years previously underwent ERCP with biliary manometry, bile sampling, and biopsy. Manometry was performed using a perfused triple-lumen manometry catheter and a station pull-through technique. Bile samples were cultured and analyzed for biliary lipids, bile salts, bacterial beta-glucuronidase, and phospholipase A2. Biopsy specimens were taken from the proximal common heptic duct for histologic examination. Manometry demonstrated absent basal sphincter pressure and no choledochoduodenal pressure gradient in all patients. Phasic contractions were observed in two patients. Cholangiography showed stones in one patient. Positive cultures were obtained in three patients, including the patient with stones. All bile samples showed a high content of biliary lipids and cholesterol. Some samples contained considerable amounts of hydrophobic bile salts. Five samples contained very high levels of phospholipase A2 activity. Significant bacterial beta-glucuronidase activity was found in one patient, the patient with stones. Biopsy specimens of the proximal common hepatic duct in three patients showed chronic inflammation with fibrosis and reactive epithelial changes. After endoscopic sphincterotomy for bile duct stones, the function of the biliary sphincter is permanently lost. This is associated with bacterial colonization, presence of cytotoxic components in the bile, and chronic inflammation of the biliary system.


Maternal-fetal distribution of morphine and alfentanil in near-term sheep and rhesus monkeys.
Maternal-fetal distribution of the opiate agents morphine and alfentanil was studied in 3 near-term sheep and rhesus monkeys. Blood samples were obtained from maternal and fetal arteries for radioimmunoassay after placement of catheters under halothane anesthesia. Fetal-maternal ratios (F/M) of plasma morphine concentrations for sheep increased from 0.04 to 0.47 during the first hour after bolus IV injection of 200 micrograms/kg morphine. However, in monkeys, F/M values were considerably higher, increasing from 0.27 to 1.85. Indeed, values over 1.00, indicating higher drug concentrations in fetal than maternal plasma, were seen in two monkeys at 10 and 60 min time points. For alfentanil, a more lipid soluble but highly protein-bound drug, F/M values of plasma concentrations were similar in the two species ranging from 0.1 to 0.6 after injection of 250 micrograms/kg in sheep and 125 micrograms/kg in monkeys. Quantitation of morphine glucuronide, the principal metabolite of morphine and total morphine-like immunoactivity, suggested that morphine was metabolized more rapidly in monkey dams than in sheep, and that morphine glucuronide was more readily distributed to monkey than sheep fetus. These data suggest that morphine, but not alfentanil, transfers more readily from dam to fetus in near-term monkeys than in sheep.


The NINDS Parkinson's disease biomarkers program.
Neuroprotection for Parkinson's disease (PD) remains elusive. Biomarkers hold the promise of removing roadblocks to therapy development. The National Institute of Neurological Disorders and Stroke has therefore established the Parkinson's Disease Biomarkers Program to promote discovery of PD biomarkers for use in phase II and III clinical trials. Using a novel consortium design, the Parkinson's Disease Biomarker Program is focused on the development of clinical and laboratory-based biomarkers for PD diagnosis, progression, and prognosis. Standardized operating procedures and pooled reference samples were created to allow cross-project comparisons and assessment of batch effects. A web-based Data Management Resource facilitates rapid sharing of data and biosamples across the research community for additional biomarker projects. Eleven consortium projects are ongoing, seven of which recruit participants and obtain biosamples. As of October 2014, 1,082 participants have enrolled (620 PD, 101 with other causes of parkinsonism, 23 essential tremor, and 338 controls), 1,040 of whom have at least one biosample. Six thousand eight hundred ninety-eight total biosamples are available from baseline, 6-, 12-, and 18-month visits: 1,006 DNA, 1,661 RNA, 1,419 whole blood, 1,382 plasma, 1,200 serum, and 230 cerebrospinal fluid (CSF). Quality control analysis of plasma, serum, and CSF samples indicates that almost all samples are high quality (24 of 2,812 samples exceed acceptable hemoglobin levels). By making samples and data widely available, using stringent operating procedures based on existing standards, hypothesis testing for biomarker discovery, and providing a resource that complements existing programs, the Parkinson's Disease Biomarker Program will accelerate the pace of PD biomarker research. © 2015 International Parkinson and Movement Disorder Society.